Searching for genetic clues to the causes of pre-eclampsia

Chappell, Sally; Morgan, Linda

doi:10.1042/cs20050323

Cited by 156 publications

(148 citation statements)

References 115 publications

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“…Finally, a host of publications suggest that genetic variants in RAS-related genes contribute to preeclampsia. 30 These observations, coupled with our own findings concerning the existence of AT1-AA, prompted this investigation. 10 Gant et al 31 had a major influence on the concept of RAS involvement in preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia

et al. 2007

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Abstract-The renin-angiotensin system (RAS) participates in preeclampsia; however, the relative contributions from the circulating RAS and the tissue-based, uteroplacental RAS are unknown. We hypothesized that the tissue-based uteroplacental RAS is dysregulated in preeclampsia. We performed microarray and gene expression studies and confirmed the findings on the protein level by immunohistochemistry in ureteroplacental units from 10 preeclamptic women and 10 women with uneventful pregnancies. All of the women were delivered by cesarean section. We also analyzed plasma renin activity and circulating agonistic angiotensin II type 1 (AT 1 ) receptor autoantibodies. In preeclampsia, we found that the angiotensin II AT 1 receptor gene was 5-fold upregulated in decidua (maternal origin). We also found AT 1 autoantibodies in preeclamptic women and in their offspring by neonatal cardiomyocyte bioassay compared with women with normal pregnancies and their infants (mother: 17.5Ϯ2.2 versus 0.05Ϯ0.4; fetus: 14.5Ϯ1.8 versus 0.5Ϯ0.5 ⌬bpm). Gene expressions for renin (35.0-fold), angiotensin-converting enzyme (2.9-fold), and angiotensinogen (8.9-fold) were higher in decidua than placenta (fetal origin) in both control and preeclamptic women, whereas the AT 1 receptor was expressed 10-fold higher in placenta than in decidua in both groups. Our findings elucidate the ureteroplacental unit RAS in preeclamptic and normal pregnancies. We found that, in preeclampsia, the AT 1 receptor expression is particularly high in decidua, combined with pregnancy-specific tissue RAS involving decidual angiotensin II production and AT 1 autoantibodies. We also showed that AT 1 autoantibodies cross the ureteroplacental barrier. These components could participate in the pathophysiology of preeclampsia.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia

et al. 2007

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“…Adjustment for birth weight and adiposity reduced the association by a small amount, and a moderate effect persisted, although statistical significance was lost. Thus, possible alternative explanations include metabolic changes in the fetus due to the preeclamptic intrauterine environment leading to an increased risk for type 2 diabetes or genetic susceptibility for preeclampsia predisposing offspring of preeclamptic mothers to hypertension, insulin resistance, and glucose intolerance (35).…”

Section: Methodological Considerationsmentioning

confidence: 99%

Prenatal Exposures and Glucose Metabolism in Adulthood

Thomas¹,

Hyppönen²,

Power³

2007

Diabetes Care

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OBJECTIVE -Birth weight has been associated with the risk of type 2 diabetes in several studies. We investigated whether prenatal influences on birth weight (gestational age, parity, preeclampsia, prepregnancy BMI, smoking during pregnancy, and socioeconomic position [SEP]) were associated with glucose metabolism in midlife and the role of birth weight for gestational age (BGA) and adult adiposity in mediating these associations. RESEARCH DESIGN AND METHODS -Data from 7,518 participants of the 1958British Birth Cohort with information on A1C at age 45 years were analyzed. Associations between prenatal exposures and A1C Ն6% were examined using a series of logistic regression models. The basic model consisted of all prenatal factors (except parity) adjusted for sex and family history of type 2 diabetes. Further adjustments included BGA only, concurrent adiposity only (BMI and waist circumference), and BGA plus adiposity. were independently associated with A1C at 45 years of age. Adjustment for BGA had little impact on the prenatal factors/A1C associations, whereas adjustment for adult adiposity at 45 years substantially reduced associations for prepregnancy BMI, smoking during pregnancy, and SEP. RESULTSCONCLUSIONS -Prenatal exposures were related to blood glucose levels in midadulthood. Associations for several prenatal factors were largely mediated through adult adiposity but surprisingly not through birth weight. Prenatal exposures are likely to have the strongest effect on glucose metabolism indirectly through their influence on adiposity. Diabetes Care 30:918 -924, 2007

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“…endothelial dysfunction and inflammation) [10,11], and tend to occur in the same families [12]. These common antecedents have drawn attention to the likelihood of shared genetic susceptibility [13,14]. Supporting this notion are several cardiovascular risk factors present years before a preeclamptic pregnancy, including increased blood pressure, higher levels of serum cholesterol, higher levels of low density lipoprotein (LDL)-cholesterol and higher levels of triglycerides [15].…”

Section: Introductionmentioning

confidence: 99%

Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22

Løset

Johnson

Melton

et al. 2014

Pregnancy Hypertension: An International Journal of Women's Car

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Objective: Four putative single nucleotide polymorphism (SNP) risk variants at the preeclampsia susceptibility locus on chromosome 2q22; rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preeclampsia risk variants in an independent Australian population-based cohort. Methods:The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1,246 mothers and 1,404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software.Results: Nominal associations (P < 0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P = 0.005) and decreased blood glucose levels in adolescents (P = 0.022). The LRP1B SNP was associated with increased maternal height (P = 0.026) and decreased maternal weight (P = 0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P = 0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preeclamptic pregnancy (P = 0.003) and having a mother with prior preeclamptic pregnancy (P = 0.033). Conclusions:Our collective findings support the hypothesis that genetic mechanisms for preeclampsia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P < 0.001).

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Searching for genetic clues to the causes of pre-eclampsia

Cited by 156 publications

References 115 publications

Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia

Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia

Prenatal Exposures and Glucose Metabolism in Adulthood

Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22

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